HYDROGEN PEROXIDE ACTIVATION OF THE STAT PATHWAY

活性氧类与多种疾病有关，包括 动脉粥样硬化，成人呼吸窘迫综合征，肺纤维化， 和阿尔茨海默氏症。活性氧还具有生理作用和 甚至可能在细胞代谢中起到第二信使的作用。虚拟 所有活着的有机体都被发现能迅速激活新基因 对氧化应激反应的转录。其中一些基因被激活 通过活性氧，基因参与了这些物种的解毒，如 如过氧化氢酶和超氧化物歧化酶。在哺乳动物细胞中 已知的参与调节的转录因子 即刻早期基因也被活性氧激活。这些措施包括 核因子KappaB和AP-1复合体。最近一个新的转录家族 称为统计量的因子(用于信号转换器和激活器 转录)已被描述为调节部分 对生长因子和细胞因子的转录反应。我们发现了 在成纤维细胞中，Stat信号转导通路被激活 在用过氧化氢处理细胞的五分钟内。 这项提议的目的是阐明激活的机制 H_2O_2对STAT转录因子的影响及其调控基因的鉴定 H_2O_2通过激活Stat转录因子。这项提案的目的 1)确定氧化还原调节对激活的影响 通过活性氧统计2)以确定由 H_2O_2负责STAT的激活和3)了解 在对过氧化氢的转录反应中的统计信息。

Reactive oxygen species are involved in a variety of diseases including atherosclerosis, adult respiratory distress syndrome, pulmonary fibrosis, and alzheimer's. Reactive oxygen species also have physiological roles and may even function as second messengers in cellular metabolism. Virtually all living organisms have been found to rapidly activate new gene transcription in response to oxidative stress. Some of the genes activated by reactive oxygen are genes involved in detoxifying these species, such as catalase and superoxide dismutase. In mammalian cells several transcription factors that are known to be involved in the regulation of immediate early genes are also activated by reactive oxygen. These include NF Kappa B and the AP-1 complex. Recently a new family of transcription factors, called Stats (for Signal transducers and activators of transcription) has been described that mediates part of the transcriptional response to growth factors and cytokines.. We have found that in fibroblasts, the Stat signal transduction pathway is activated within five minutes of treatment of cells with hydrogen peroxide. The goals of this proposal are to elucidate the mechanisms of activation of the Stat transcription factors by H2O2 and to identify genes regulated by H2O2 via Stat transcription factor activation. The aims of the proposal are 1) to identify the redox regulatory influences on the activation of Stats by reactive oxygen 2) to identify the tyrosine kinases activated by H2O2 responsible for Stat activation and 3) to understand the role of the Stats in the transcriptional response to H2O2.